Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats Fruzsina K Johnson1*, Robert A Johnson1, William Durante2, Keith E Jackson1, Blake K Stevenson1, and Kelly J Peyton2 1 Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA, USA 2 Departments of Medicine and Pharmacology, Baylor College of Medicine, Houston, TX, USA * To whom correspondence should be addressed. E-mail: fjohnson@cvlabs.org. Vascular heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Increased heme-derived CO inhibits nitric oxide synthase and can contribute to hypertension via endothelial dysfunction in Dahl salt-sensitive rats. Obese Zucker rats (ZR) are models of metabolic syndrome. This study tests the hypothesis that endogenous CO formation is increased and contributes to hypertension and endothelial dysfunction in obese ZR. Awake obese ZR showed increased respiratory CO excretion which was lowered by HO inhibitor administration (ZnDPBG 25µmol/kg/24hr ip). In awake obese ZR, chronically instrumented with femoral arterial catheters, blood pressure was elevated and was decreased by the HO inhibitor, ZnDPBG. Body weight, blood glucose, HbA1c, plasma insulin, total and LDL cholesterol, oxidized LDL, and triglyceride levels were elevated in obese ZR, and, except for LDL cholesterol, were unchanged by HO inhibition. Total HO-1 protein levels were not different between lean and obese ZR aortas. In vitro experiments used isolated skeletal muscle arterioles with constant pressure and no flow, or constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow. In obese ZR arterioles, responses to acetylcholine and flow were attenuated. Acute in vitro pretreatment with a HO inhibitor, CrMP, enhanced acetylcholine and flow-induced dilation and abolished the differences between groups. Furthermore, exogenous CO prevented the restoration of flow-induced dilation by the HO inhibitor in obese ZR arterioles. These results suggest that HO-derived CO production is increased and promotes hypertension and arteriolar endothelial dysfunction in obese ZR with metabolic syndrome independent of affecting metabolic parameters.